Abstract 3179: Tumor educated lung epithelial cells promote osteosarcoma metastasis and chemotherapy resistance by inducing integrin dependent fibronectin fibrillogenesis

Abstract

Abstract Metastasis is the leading cause of cancer related deaths for patients with solid tumors. While tumor genomic evolution is one possible mechanism whereby cancer cells acquire chemotherapy resistance during the metastatic process, increasing evidence demonstrates that non-cancerous cells within the secondary organ have crucial roles in mediating metastasis and therapy resistance. Therefore, disrupting tumor-stromal cell interactions is an exploitable therapeutic strategy to improve outcomes. Unfortunately, mechanistic insight into tumor-stromal interactions is limited for most cancers. Osteosarcoma, an aggressive bone tumor that primarily afflicts children and young adults, displays an overwhelming propensity for metastasis to the lungs, with overall survival plummeting to less than 20% at 5 years upon lung metastasis. Why osteosarcoma displays tropism for the lung and how it educates the lung to promote tumor growth in a vastly different microenvironment from the primary tumor remains poorly understood. In this study, we utilized single-cell RNA sequencing to define the cellular and molecular landscape of osteosarcoma metastases in immunocompetent mouse models. We unexpectedly found that alveolar epithelial cells are the most prominent non-immune stromal component within lung metastases. Not only are they present in significant numbers in lung metastases compared to unaffected lung, our molecular analysis demonstrated that tumor associated epithelial cells acquire a pro-fibrosis ‘wound-like’ phenotype, which was also observed in human metastasis samples. Furthermore, utilizing human and mouse culture systems, we found that osteosarcoma cells directly reprogramed epithelial cells through secretion of growth factors and cytokines such as FGF7 and IL6. These profibrotic epithelial cells in turn induced osteosarcoma cells to generate a complex, beta-1integrin (ITGB1)- dependent fibronectin matrix. The epithelial induced fibronectin matrix promoted osteosarcoma invasion and chemotherapy resistance. Accordingly, inhibition of ITGB1 sensitized osteosarcoma cells to chemotherapy. Collectively our results demonstrate that osteosarcoma cells educate the lung microenvironment into a ‘pro-wound’, pro-fibrosis state that is conducive to osteosarcoma lung colonization. Disruption of the lung metastatic niche is a promising therapeutic target for sensitizing osteosarcoma cells to chemotherapy. Citation Format: James Brandon Reinecke, Amy Gross, Maren Cam, Ryan Roberts. Tumor educated lung epithelial cells promote osteosarcoma metastasis and chemotherapy resistance by inducing integrin dependent fibronectin fibrillogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3179.